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The synergistic immunoregulatory effects of culture-expanded mesenchymal stromal cells and CD4(+)25(+)Foxp3+ regulatory T cells on skin allograft rejection.

Lee JH, Jeon EJ, Kim N, Nam YS, Im KI, Lim JY, Kim EJ, Cho ML, Han KT, Cho SG - PLoS ONE (2013)

Bottom Line: Mesenchymal stromal cells (MSCs) are seen as an ideal source of cells to induce graft acceptance; however, some reports have shown that MSCs can be immunogenic rather than immunosuppressive.Our results show that allograft survival was significantly longer in group D compared to the control group (group A).Taken together, these data suggest that a combined cell therapy approach with MSCs and Tregs has a synergistic effect on immunoregulatory function in vivo, and might provide a novel strategy for improving survival in allograft transplantation.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Immune Regulation, Convergent Research Consortium for Immunologic Disease, Seoul St Mary's Hospital, The Catholic University of Korea College of Medicine, Seoul, Korea.

ABSTRACT
Mesenchymal stromal cells (MSCs) are seen as an ideal source of cells to induce graft acceptance; however, some reports have shown that MSCs can be immunogenic rather than immunosuppressive. We speculate that the immunomodulatory effects of regulatory T cells (Tregs) can aid the maintenance of immunoregulatory functions of MSCs, and that a combinatorial approach to cell therapy can have synergistic immunomodulatory effects on allograft rejection. After preconditioning with Fludarabine, followed by total body irradiation and anti-asialo-GM-1(ASGM-1), tail skin grafts from C57BL/6 (H-2k(b)) mice were grafted onto the lateral thoracic wall of BALB/c (H-2k(d)) mice. Group A mice (control group, n = 9) did not receive any further treatment after preconditioning, whereas groups B and C (n = 9) received cell therapy with MSCs or Tregs, respectively, on days -1, +6 and +13 relative to the skin transplantation. Group D (n = 10) received cell therapy with MSCs and Tregs on days -1, +6 and +13. Cell suspensions were obtained from the spleens of five randomly chosen mice from each group on day +7, and the immunomodulatory effects of the cell therapy were evaluated by flow cytometry and real-time PCR. Our results show that allograft survival was significantly longer in group D compared to the control group (group A). Flow cytometric analysis and real-time PCR for splenocytes revealed that the Th2 subpopulation in group D increased significantly compared to the group B. Also, the expression of Foxp3 and STAT 5 increased significantly in group D compared to the conventional cell therapy groups (B and C). Taken together, these data suggest that a combined cell therapy approach with MSCs and Tregs has a synergistic effect on immunoregulatory function in vivo, and might provide a novel strategy for improving survival in allograft transplantation.

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Immunophenotypes of ex-vivo expanded retinal-induced Tregs.(A) Retinal-induced CD4+CD25+ Tregs showed >96% purity on flow cytometry. (B) Tregs generated were characterized by positive expression of intracellular Foxp3, CTLA-4, and surface expression of the indicated markers (PD-1, GITR, ICAM-1, CD44, ICOS) in the gated T-cell populations. Also, they showed weak positive surface staining for CD62L and CD103. The percentages indicate numbers of double-positive cells.
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pone-0070968-g002: Immunophenotypes of ex-vivo expanded retinal-induced Tregs.(A) Retinal-induced CD4+CD25+ Tregs showed >96% purity on flow cytometry. (B) Tregs generated were characterized by positive expression of intracellular Foxp3, CTLA-4, and surface expression of the indicated markers (PD-1, GITR, ICAM-1, CD44, ICOS) in the gated T-cell populations. Also, they showed weak positive surface staining for CD62L and CD103. The percentages indicate numbers of double-positive cells.

Mentions: Culture-expanded MSCs showed a typical fibroblast-like morphology and were uniformly positive for Sca-1, CD44, and CD29, but negative for c-Kit, CD11b, CD34, CD106, CD45, and CD 31(Fig. 1). Retinal-induced CD4+CD25+ Tregs showed >96% purity on flow cytometry and positive surface staining for several phenotypic Treg markers, including CD44, 1–3glucocorticoid-induced tumor necrosis factor receptor (GITR), intercellular adhesion molecule-1 (ICAM-1), inducible costimulator (ICOS) and programmed death-1 (PD-1). Also, they showed weak positive surface staining for CD62L and CD103 (Fig. 2).


The synergistic immunoregulatory effects of culture-expanded mesenchymal stromal cells and CD4(+)25(+)Foxp3+ regulatory T cells on skin allograft rejection.

Lee JH, Jeon EJ, Kim N, Nam YS, Im KI, Lim JY, Kim EJ, Cho ML, Han KT, Cho SG - PLoS ONE (2013)

Immunophenotypes of ex-vivo expanded retinal-induced Tregs.(A) Retinal-induced CD4+CD25+ Tregs showed >96% purity on flow cytometry. (B) Tregs generated were characterized by positive expression of intracellular Foxp3, CTLA-4, and surface expression of the indicated markers (PD-1, GITR, ICAM-1, CD44, ICOS) in the gated T-cell populations. Also, they showed weak positive surface staining for CD62L and CD103. The percentages indicate numbers of double-positive cells.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3733648&req=5

pone-0070968-g002: Immunophenotypes of ex-vivo expanded retinal-induced Tregs.(A) Retinal-induced CD4+CD25+ Tregs showed >96% purity on flow cytometry. (B) Tregs generated were characterized by positive expression of intracellular Foxp3, CTLA-4, and surface expression of the indicated markers (PD-1, GITR, ICAM-1, CD44, ICOS) in the gated T-cell populations. Also, they showed weak positive surface staining for CD62L and CD103. The percentages indicate numbers of double-positive cells.
Mentions: Culture-expanded MSCs showed a typical fibroblast-like morphology and were uniformly positive for Sca-1, CD44, and CD29, but negative for c-Kit, CD11b, CD34, CD106, CD45, and CD 31(Fig. 1). Retinal-induced CD4+CD25+ Tregs showed >96% purity on flow cytometry and positive surface staining for several phenotypic Treg markers, including CD44, 1–3glucocorticoid-induced tumor necrosis factor receptor (GITR), intercellular adhesion molecule-1 (ICAM-1), inducible costimulator (ICOS) and programmed death-1 (PD-1). Also, they showed weak positive surface staining for CD62L and CD103 (Fig. 2).

Bottom Line: Mesenchymal stromal cells (MSCs) are seen as an ideal source of cells to induce graft acceptance; however, some reports have shown that MSCs can be immunogenic rather than immunosuppressive.Our results show that allograft survival was significantly longer in group D compared to the control group (group A).Taken together, these data suggest that a combined cell therapy approach with MSCs and Tregs has a synergistic effect on immunoregulatory function in vivo, and might provide a novel strategy for improving survival in allograft transplantation.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Immune Regulation, Convergent Research Consortium for Immunologic Disease, Seoul St Mary's Hospital, The Catholic University of Korea College of Medicine, Seoul, Korea.

ABSTRACT
Mesenchymal stromal cells (MSCs) are seen as an ideal source of cells to induce graft acceptance; however, some reports have shown that MSCs can be immunogenic rather than immunosuppressive. We speculate that the immunomodulatory effects of regulatory T cells (Tregs) can aid the maintenance of immunoregulatory functions of MSCs, and that a combinatorial approach to cell therapy can have synergistic immunomodulatory effects on allograft rejection. After preconditioning with Fludarabine, followed by total body irradiation and anti-asialo-GM-1(ASGM-1), tail skin grafts from C57BL/6 (H-2k(b)) mice were grafted onto the lateral thoracic wall of BALB/c (H-2k(d)) mice. Group A mice (control group, n = 9) did not receive any further treatment after preconditioning, whereas groups B and C (n = 9) received cell therapy with MSCs or Tregs, respectively, on days -1, +6 and +13 relative to the skin transplantation. Group D (n = 10) received cell therapy with MSCs and Tregs on days -1, +6 and +13. Cell suspensions were obtained from the spleens of five randomly chosen mice from each group on day +7, and the immunomodulatory effects of the cell therapy were evaluated by flow cytometry and real-time PCR. Our results show that allograft survival was significantly longer in group D compared to the control group (group A). Flow cytometric analysis and real-time PCR for splenocytes revealed that the Th2 subpopulation in group D increased significantly compared to the group B. Also, the expression of Foxp3 and STAT 5 increased significantly in group D compared to the conventional cell therapy groups (B and C). Taken together, these data suggest that a combined cell therapy approach with MSCs and Tregs has a synergistic effect on immunoregulatory function in vivo, and might provide a novel strategy for improving survival in allograft transplantation.

Show MeSH
Related in: MedlinePlus